Subthreshold contribution of N-methyl--aspartate receptors to long-term potentiation induced by low-frequency pairing in rat hippocampal CA1 pyramidal cells

Abstract

Long-term potentiation (LTP) is a use-dependent and persistent enhancement of synaptic strength. In the CA1 region of the hippocampus, LTP has Hebbian characteristics and requires precisely timed interaction between presynaptic firing and postsynaptic depolarization. Although depolarization is an absolute requirement for plasticity, it is still not clear whether the postsynaptic response during LTP induction should be subthreshold or suprathreshold for the generation of somatic action potential. Here, we use the whole-cell patch-clamp technique and different pairing protocols to examine systematically the postsynaptic induction requirements for LTP. We induce LTP by changes only in membrane potential while keeping the afferent stimulation constant and at minimal levels. This approach permits differentiation of two types of LTP: LTP induced with suprathreshold synaptic responses (LTPAP) and LTP induced with subthreshold excitatory postsynaptic current (EPSCs; LTPEPSC). We found that LTPAP (>40%) required pairing of depolarization (Vm≥−40 mV, for 40–60 s) with four to six (0.1 Hz) single synaptically initiated action potentials. LTPEPSC was of smaller magnitude (<30%) and required pairing of depolarization to −50 mV (60 s) with six subthreshold EPSCs. The N-methyl-d-aspartate receptor (NMDAR) antagonists aminophosphonovaleric acid and 7-chlorokynurenic acid consistently blocked LTPEPSC but were ineffective in preventing LTPAP. Robust, NMDAR-independent LTP is obtained by stronger postsynaptic depolarization that converts the EPSCs to suprathreshold somatic action potentials. Purely NMDAR-dependent LTP is obtained by pairing mild somatic depolarization with subthreshold afferent pulses to the postsynaptic cell. Our results indicate that the degree of postsynaptic depolarization in the presence of single afferent pulses determines the type and magnitude of LTP.